Involvement of the MEK-ERK/p38-CREB/c-fos signaling pathway in Kir channel inhibition-induced rat retinal Müller cell gliosis.
Involvement of the MEK-ERK/p38-CREB/c-fos signaling pathway in Kir channel inhibition-induced rat retinal Müller cell gliosis.
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MEK-ERK/p38-CREB/c-fos信号通路参与Kir通道抑制诱导的大鼠视网膜Muller细胞胶质增生
DOI：
10.1038/s41598-017-01557-y
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发表时间：
2017-05-03
影响因子：
4.6
通讯作者：
Wang Z
中科院分区：
文献类型：
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作者：
Gao F;Li F;Miao Y;Xu LJ;Zhao Y;Li Q;Zhang SH;Wu J;Sun XH;Wang Z
我们以前的研究表明，I组代谢型谷氨酸受体的激活下调Kir通道在慢性高眼压（COH）大鼠，从而有助于Müller细胞胶质增生，其特征是上调表达的胶质细胞酸性蛋白（GFAP）。在本研究中，我们探讨了可能的信号通路连接Kir通道抑制和GFAP上调。在正常视网膜中，玻璃体内注射BaCl 2显著增加了Müller细胞中GFAP的表达，这被共注射丝裂原活化蛋白激酶（MAPK）抑制剂U 0126所消除。磷酸化的细胞外信号调节蛋白激酶1/2（p-ERK 1/2）及其上游调节因子p-MEK的蛋白水平显著增加，而磷酸化的c-Jun N-末端激酶（p-JNK）和p38激酶（p-p38）的水平保持不变。此外，磷酸化的cAMP反应元件结合蛋白（p-CREB）和c-fos的蛋白水平也增加，这被共同注射ERK抑制剂FR 180204阻断。在纯化培养的大鼠Müller细胞中，BaCl 2处理诱导这些蛋白质水平的类似变化，除了p-p38水平和p-p38：p38比率显示显著上调。此外，玻璃体内注射U 0126消除了COH视网膜中上调的GFAP表达。总之，这些结果表明Kir通道抑制诱导的Müller细胞神经胶质增生是由MEK-ERK/p38-CREB/c-fos信号通路介导的。
Our previous studies have demonstrated that activation of group I metabotropic glutamate receptors downregulated Kir channels in chronic ocular hypertension (COH) rats, thus contributing to Müller cell gliosis, characterized by upregulated expression of glial fibrillary acidic protein (GFAP). In the present study, we explored possible signaling pathways linking Kir channel inhibition and GFAP upregulation. In normal retinas, intravitreal injection of BaCl2 significantly increased GFAP expression in Müller cells, which was eliminated by co-injecting mitogen-activated protein kinase (MAPK) inhibitor U0126. The protein levels of phosphorylated extracellular signal-regulated protein kinase1/2 (p-ERK1/2) and its upstream regulator, p-MEK, were significantly increased, while the levels of phosphorylated c-Jun N-terminal kinase (p-JNK) and p38 kinase (p-p38) remained unchanged. Furthermore, the protein levels of phosphorylated cAMP response element binding protein (p-CREB) and c-fos were also increased, which were blocked by co-injecting ERK inhibitor FR180204. In purified cultured rat Müller cells, BaCl2 treatment induced similar changes in these protein levels apart from p-p38 levels and the p-p38:p38 ratio showing significant upregulation. Moreover, intravitreal injection of U0126 eliminated the upregulated GFAP expression in COH retinas. Together, these results suggest that Kir channel inhibition-induced Müller cell gliosis is mediated by the MEK-ERK/p38-CREB/c-fos signaling pathway.